Helminths are multicellular pathogens that cause significant human disease in the Developing World, where 2 billion people are infected with helminths of various species. Schistosomes account for 10% of all helminth infections, infecting approximately 200 million people globally. Less complex pathogens, such as bacteria and viruses, express conserved pathogen-associated molecular patterns (PAMPs) that bind host pattern recognition receptors (PRRs, e.g. toll-like receptors (TLRs)) and induce pro-inflammatory CD4+ T helper (Th) 1 responses. In contrast, helminths do not express readily recognizable PAMPs, do not activate classical PRRs and instead induce Th2 and immunomodulatory responses. Indeed, the almost ubiquitous induction of Th2 responses by helminths has led to the hypothesis that Th2 responses evolved as a defense against helminths. Consistent with this hypothesis, there is evidence that Th2 responses can mediate immunological protection against helminth infection and may mitigate the pathology associated with helminth infection. However, the helminth- specific signals that drive Th2 polarization are poorly understood. In some helminths, specific parasite molecules that drive Th2 polarization have been identified, but whether a common underlying mechanism is involved in Th2 induction by helminths in general is unclear. In many helminths, including nematodes and flatworms such as schistosomes, cysteine proteases play a central role in host invasion and acquisition of nutrients and are frequently secreted into the extracellular space to fulfill these roles. Because vertebrate hosts do not normally secrete cysteine proteases but maintain these enzymes under tight control within intracellular compartments, it is hypothesized that the vertebrate immune system has evolved to recognize extracellular cysteine proteases as immunostimulatory pathogen-associated motifs, akin to TLR ligands, but which preferentially induce Th2 rather than Th1 responses. This hypothesis is supported by the observation that cysteine protease activity is also associated with many Th2-inducing allergens, and that cysteine proteases derived from non-helminth sources such as plants also induce Th2 responses. However, direct evidence that helminth cysteine proteases play a role in Th2 response induction during helminth infection is lacking. We recently demonstrated that Schistosoma mansoni cathepsin B1 (SmCB1), a major secreted cysteine protease of S. mansoni, is a dominant antigen during the early stages of schistosome infection and is rapidly targeted by a Th2 response, resulting in production of SmCB1-specific IgE and sensitization of basophils to produce interleukin (IL)-4 in response to schistosome antigens. We therefore hypothesize that SmCB1 is implicated in polarizing the CD4+ T cell response towards a Th2 phenotype during schistosome infection. We propose to test this hypothesis by testing (i) whether SmCB1 protein and its associated protease activity are required for induction of a parasite-specific Th2 response during the early stages of infection, and (ii) whether SmCB1 has intrinsic Th2-inducing properties that are dependent on its protease activity. Our findings may have broad implications for understanding how Th2 responses are induced. Furthermore, as cysteine proteases are readily targeted pharmacologically, our findings may identify novel approaches to modulating Th2 responses during schistosome infection, which might be beneficial in augmenting anti-helminth immunity or mitigating the pathology that is associated with dysregulated Th2 responses.